DESCRIPTION (applicant's abstract): Repeated administration of cocaine produces enduring changes in behavior, including a progressive increase in cocaine-induced motor stimulation. The underlying neuroadaptations mediating motor sensitization in rodents have been proposed to contribute to behaviors associated with cocaine addiction, such as paranoia and craving. Knowledge that monoamine transporters constitute the molecular binding site for cocaine has focused investigation of the cellular underpinnings of behavioral sensitization on dopamine transmission in the nucleus accumbens. Although this research endeavor has revealed many long-lasting neuroadaptations in dopamine transmission that contribute to behavioral sensitization, it has become clear that the focus on neither dopamine nor the nucleus accumbens provides a complete profile of cocaine-induced neuroadaptations mediating addiction. To some extent exploration beyond dopamine is impelled by the realization that behavioral sensitization is potently regulated by learned associations made between the pharmacological actions of cocaine and environmental stimuli. Thus, glutamatergic cortical brain regions involved in learning and memory have become another focus in the search for substrates mediating behavioral sensitization to cocaine. This proposal will evaluate an overarching hypothesis that the enduring changes in pre- and post-synaptic glutamate transmission in the nucleus accumbens and adjacent circuitry mediate behavioral sensitization to cocaine. Three general experiments will be performed. 1) The mechanisms mediating cocaine-induced changes in vesicular- and transporter-mediated glutamate release will be examined. 2) The effect of repeated cocaine on proteins involved in glutamate receptor signaling will be examined and adenovirus gene transfer will be employed to evaluate the role of these proteins in behavioral sensitization. 3) The role that glutamate transmission plays in the conditioned motor responses associated with repeated cocaine administration will be examined.